This is a time-sensitive RFI directed toward determining key factors regarding gene expression mapping of the developing rhesus macaque brain. Responses to this RFI should be pertinent to the interests of one or more of the NIH Neuroscience Blueprint Organizations listed above.

Neuroscience research is a unifying theme across many NIH Institutes and Centers (ICs). The NIH Blueprint for Neuroscience Research was launched in 2004, and now includes 15 Institutes and Centers as well as the Office of Behavioral and Social Science Research. The Blueprint provides a framework for prospectively coordinating research of common interest, including the development of tools and resources which are broadly useful for advancing neuroscience research (http://neuroscienceblueprint.nih.gov/ ). To this end, the Blueprint pools resources and expertise to take advantage of economies of scale and address cross-cutting needs of the research community. Through a series of focused Blueprint initiatives, a variety of new tools and resources have already been made available to neuroscientists. In Fiscal Year 2008, the Blueprint will generate and make available novel research tools and resources to rapidly advance the field of nervous system development. Such tools and resources will be critical for improved comprehension of normal development, as well as for the elucidation of a wide array of nervous system disorders based in aberrant developmental processes.

Information Requested

The NIH Blueprint ICs share an interest in understanding normal nervous system developmental processes, as well as how abnormal developmental trajectories may affect physical and emotional health across the lifespan. There is an identified need for knowledge of detailed localization of gene expression in the developing human nervous system, with the long-term goal being to obtain detailed and searchable maps of gene expression in human brain. However, given the size and complexity of the human nervous system, straightforward adoption of available techniques is both premature and cost-prohibitive. A tractable, near-term alternative would be to initiate pilot studies in specific brain regions/circuits in developing nonhuman primate brain, such that accumulated data would be represented in a digital brain atlas with associated informatics tools to facilitate data searches and analyses. The recent sequencing of the genome of the Rhesus macaque, Macaca mulatta, as well as its broad application as a research model, suggest that this nonhuman primate species would provide the optimal translational bridge between existing gene expression atlases in other species, including mouse, and future efforts in human. Ideally, these pilot studies will have a unique and significant impact on our knowledge of primate brain development.

In order to establish a strong foundation for this pilot project, the NIH Blueprint will focus initial efforts on a limited number of brain regions. This early focus will include two well-defined regions, hippocampus and primary visual cortex, a less well-defined region, the medial prefrontal cortex, and possibly a limited number of additional regions, for the establishment of a developmental gene expression atlas of Rhesus brain. Within the field of developmental neurobiology, the hippocampus and the primary visual cortex represent useful starting points, due to their well-defined gross anatomy (allowing for valid dissection), detailed circuitry, established relationships between circuitry and specific functions, and existing knowledge of critical periods of development across different species. In addition, because gene expression is most easily mapped in anatomically well-characterized regions, these two structures will provide a template by which developmental rules in other, less well-defined structures can be established. Finally, improved knowledge of each of these regions has broad implications for the developmental neurobiology of the human brain. The hippocampus and medial prefrontal cortex are crucial for a wide range of functions, including learning and memory, cognition emotion, social behavior, and executive function. The primary visual cortex, which is classically utilized to parse the impact of genes and environment on brain development, serves as a model for understanding the broader neural networks of the neocortex, which is associated with higher brain function in humans. Therefore, the NIH Neuroscience Blueprint seeks input from the scientific community on specific parameters for the characterization of developmental gene expression in these structures, as well as suggestions for the inclusion of additional regions that will elucidate broader questions in primate developmental neurobiology relevant to health and disease.

With these goals in mind, as part of the planning process for Blueprint activities related to neurodevelopment, participating NIH Institutes and Centers request responses to the questions below:

1. Considering the hippocampus, medial prefrontal cortex, and primary visual cortex, and the overall intent of this project, which developmental time points and genes should receive priority for analysis? Are probes available for these genes of choice?

2. What additional brain regions or circuits would serve as the useful starting points for a developmental gene expression atlas in the rhesus macaque? How would the selection of these regions complement our present understanding of human brain development?

3. What are the critical periods of development in these regions suggested in response to Question 2? What developmental epochs should be chosen for analysis?

4. What genes and/or gene families should serve as initial targets for gene expression analysis for regions identified in response to Question 2? Are probes available for these genes of choice?

5. Are there other ongoing, related efforts that could be integrated into this effort?